(Investigator's Abstract): The goal of this application is to identify novel compounds which selectively interact with the opiate-like orphan receptor (ORL-1) for potential use as novel analgesics. The ORL-1 receptor is aprotein which shares 65 percent homology with known opiate receptors, but at present its physiological function is uncertain. Nociceptin or orphaning FQ is the endogenous ligand for the ORL-1 receptor, and they will use [3H]nociceptin and membranes from mammalian cells stably expressing the cloned human ORL-1 receptor to validate a binding assay for high throughput screening of various compound files. Compounds for testing will be peptides, peptidomimetics and nonpeptidic compounds obtained from commercial and proprietary sources. Potent and specific inhibitors of binding to the ORL-1 receptor will be used to characterize the physiological role(s) of ORL-1 receptors as an aid in the identification of potential therapeutic applications for agonists or antagonists. Specificity will be determined by evaluation of the active compounds in receptor binding assays using other cloned human opiate receptors available at Adolor. ORL-1- mediated changes in cAMP levels will show functional sequelae of the interaction with ORL-1 receptors at the cellular level and will define the nature of novel compounds as agonists or antagonists. Evaluation of nociceptin and putative ORL-1 agonists and antagonists in a battery of assays which measure analgesia and motor coordination will establish the role of nociceptin and the ORL-1 receptor in pain modulation. The discovery of compounds that bind to the ORL-1 site and function as agonists or antagonists will aid in the further elucidation of the physiological role of this binding site and its relevance to pain perception and central nervous system function.